There are several analogous compounds in tetracycline antibiotics including tetracycline per se as well as minocycline. Since they are very unstable, various studies have been conducted to stably incorporate tetracycline antibiotics into pharmaceutical compositions.
For example, Japanese Patent Laid Open Publication No. 90616/1977 discloses an aqueous injectable solution wherein teteracycline antibiotics such as oxytetracycline, doxycycline, tetracycline, chlortetracycline or a salt thereof is stabilized by chelation with an alkaline earth metal compound such as magnesium compound in an aqueous 2-pyrrolidone solution. Japanese Patent Laid Open Publication No. 94028/1978 discloses a pharmaceutical composition wherein oxytetracycline is stabilized by incorporating it with an alkaline earth metal ion, polyvinyl pyrrolidone and an aliphatic amide such as dimethylacetamide and adjusting pH to 5.0 to 7.5. Further, U.S. Pat. No. 3,335,055 discloses a method for stabilization for tetracycline with magnesium ion and a pyridine derivative such as isonicotinamide.
However, any prior art relating to the stabilization of minocycline can not be found.
By the way, since several years ago, various studies have been conducted to utilize tetracycline antibiotics in the dental field and it has been reported that, when minocycline is administered orally to a patient with a periodontal disease, a high concentration of minocycline in gingival crevicular fluid (GCF) is attained resulting in good healing [J. Periodontal., 51 (9), 530-534 (1980)]. Further, recently, it has been reported that, when minocycline is adminstered orally to a patient with a periodontal disease, an improved change in gingival inflammation and subgingival bacteria resulted [J. Periodontal. 53 (9), 557-561 (1982)].
However, these studies are based on oral administration of minocycline hydrochloride preparations and they are different from topical application of minocycline--per se directly to a lesion in the oral cavity, for example, a gingival inflammation site. Although it has been reported that tetracycline can be incorporated with polyethylmethacrylate or ethylene vinyl acetate to prepare a solid compositionn in the form of strips or fibers to be used for topical application to a lesion in the oral cavity such as periodontal pockets [J. Periodontal., 53 (11), 693-699 (1982) and 54 (10), 575-579 (1983)], this composition is insufficient for treatment and a composition containing minocycline which is suitable for direct topical application has not been found.
On the other hand, in order to treat periodontal diseases, it is desirable to directly and topically apply minocycline to a disease site in the oral cavity such as periodontal pockets to attain a high concentration of minocycline in GCF. However, as mentioned above, minocycline is a very unstable substance and no attempt has been succeeded so far to stably incorporate minocycline into a pharmaceutical composition, particularly, that suitable for topical application.
Accordingly, it has been requested, particularly in the dental field, to stabilize minocycline in a pharmaceutical composition.
Under these circumstances, the present inventors have intensively studied to obtain a pharmaceutical composition stably containing minocycline for treating periodontal diseases, which is suitable for topical application in the oral cavity. As the result, it has been found that minocycline can be stabilized by using a polyhydric alcohol containing a magnesium compound as a base of a composition and, among various tetracycline antibiotics, only minocycline is stabilized by this specific combination. Further, it has been found that the resultant composition is suitable for the treatment of periodontal diseases by topical application thereof in the oral cavity.